1. Field of the Invention
The invention relates to an improved process for the preparation of imatinib base and the pharmaceutically acceptable acid addition salts thereof. Further, the invention relates to processes for preparing intermediates in the synthesis of imatinib base and the pharmaceutically acceptable acid addition salts thereof.
2. Description of the Related Art
Imatinib, N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide, also referred to as imatinib base, is a selective inhibitor of tyrosine kinase, disclosed in EP 0564409 A1, and represented by the structural formula:

Methanesulfonic acid addition salt of imatinib is an active ingredient of oral compositions useful in the treatment of patients with Philadelphia chromosome positive chronic myeloid leukemia and with Kit-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.
Three basic synthetic pathways for preparation of imatinib base are known in the art (methods A-C).
Scheme 1 illustrates a first synthetic pathway for preparation of imatinib base, referred to herein as “Method A”. This method is known from EP 0564409 A1 and WO 2004/074502, and comprises the condensation of two chemical moieties, N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine and 4-(4-methylpiperazinelmethyl)benzoyl chloride.
Scheme 2 illustrates a second synthetic pathway for preparation of imatinib base, referred to herein as “Method B.” This method is known from WO 03/066613, and comprises condensation of 4-(3-pyridinyl)-2-pyrimidineamine, or a precursor thereof, with N-(3-bromo-4-methylphenyl)-4-(4-methylpiperazin-1-ylmethyl)-benzamide.